Alkylthiophenols are known products, used particularly as intermediates in pharmaceutical chemistry for the preparation of hypotensive and vasodilative medications, or in agrochemistry for that of herbicides or of pesticides. It is of particular importance to have access specifically to the ortho isomer or to the para isomer for these uses.
For selective preparation of each isomer, the known methods generally involve a correctly disubstituted starting material (chloronitrobenzene, nitrophenol, mercaptophenol, dichlorobenzene). These methods involve many stages and the yields obtained are often very low.
Among the many access routes to alkylthiophenols, the simplest consists in reacting a dialkyl disulphide with a phenol in the presence of a Lewis acid. However, the processes described hitherto do not make it possible to combine a good selectivity and a high degree of conversion of the starting phenol. Thus, for example, when phenol and dimethyl disulphide (DMDS) are reacted in the presence of ferric chloride or of aluminium chloride in chlorobenzene (U.S. Pat. No. 2,923,743), the ortho isomer/para isomer selectivity is only 85/15 and the yield does not exceed 48%. According to the same patent, in the absence of solvent and with a decolorizing earth (Tonsil), the para isomer predominates, but the maximum yield is 37%.
The reaction of phenol and of DMDS has also been investigated by Farah and Gilbert (Belgium Patent No. 627,306 and J. Org. Chem. 28, 2807, 1963). By using either a sulphonic acid or the P.sub.2 O.sub.5 /H.sub.3 PO.sub.4 system, or, furthermore, an acidic resin (Dowex-50 sulphonated polymer) as a Lewis acid, these authors obtained degrees of conversion on the order of 20 to 30% with a para/ortho selectivity of 82/18.
More recently (Synthesis 117, 1984 and U.S. Pat. No. 4,324,920), Ranken and McKinnie have proposed to carry out the reaction of a phenol and of a dialkyl disulphide in the absence of solvent, using an aluminium phenate as catalyst. For phenol and for DMDS, this method results in an ortho/para selectivity of 71/29; and the yields of 2-methylthiophenol are about only 40%.
On the other hand, the 4-acyl-2-alkylthiophenols used as intermediates in pharmaceutical chemistry for the synthesis of hypotensive and vasodilatative medications ca be obtained in two ways. See, for example, British Patent No. 1,544,872 and U.S. Pat. Nos. 4,124,722, 4,327,224 and 4,374,149. The first, which consists in sulphochlorinating a 4-acylphenol, then reducing the sulphonyl chloride obtained to a 4-acyl-2-mercaptophenol and in treating the latter with an alkylating agent, results in low yields. Thus, when starting with 4-acetyl-phenol, the overall yield of 4-acetyl-2-methylthiophenol (or 4-hydroxy-3-methylthioacetophenone) is only 22%. The second method, which consists in acylating a 2-alkylthiophenol directly using an acyl halide under Friedel-Crafts conditions (AlCl.sub.3 in nitrobenzene) affords better, but still very low yields (34% in the case of acetylation of 2-methylthiophenol to 4-hydroxy-3-methylthioacetophenone).
Acylation of phenol using a carboxylic acid in the presence of boron trifluoride was first described in 1933 by H. Meerwein (Ber. dtsch. Chem. Ges. 66, 411). Although this method has since been the subject of many investigations, among which there may be mentioned more particularly those of N. P. Buu-Hoi et al. (J. Org. Chem. 20, 606, 1955), E. C. Armstrong et al. (J. Am. Chem. Soc. 82, 1928, 1960), K. Freundenberg et al. (Ann. Chem. 590, 140, 1954) and K. Kindler et al. (Archiv der Pharmazie 287, 210, 1954), it has never yet been applied to 2-alkylthiophenols. Furthermore, under the conditions which are usually recommended by the literature (1 to 2 moles of BF.sub.3 /acid complex per mole of phenol), the use of this method to 2-alkylthiophenols produces only very low yields (below 40%).
The above references are hereby incorporated by reference.
It has now been found that, under certain operating conditions, the reaction of a phenol with a dialkyl disulphide enables alkylthiophenols and especially 2-alkylthiophenols to be obtained with a selectivity and in a yield which are excellent.